Chlorinated derivatives of 1-(2-{66 {hu 2{b -imidazolinyl)-2,2-diarylcyclopropanes

ABSTRACT

This invention relates to chlorinated derivatives of 1-(2- Delta 2-imidazolinyl)-2,2-diarylcyclopropanes and their acid addition salts as new industrial products, to the process for their preparation and to their therapeutic application such as antiinflammatory and anti-arrhythmic agents.

United States Patent [191 Cognaco Sept. 16, 1975 CHLORINATED DERIVATIVES OF [58] Field of Search 260/3095 1-( Z-A -IMIDAZOLINYL)-2,2-DIARYLCY- CLOPROPANES [56] References Cited [75] inventor: Jean-Claude Cognaco, Garches, OTHER PUBLICATIONS France Chem. Abstracts, 78:1 1 13121-1.

[73] Assignee: Societe Anonyme dite: Hexachime,

Rue Malmaison France Prtmary Examiner-Ethel G. Love Attorney, Agent, or Ftrm-Bacon & Thomas [22] Filed: Nov. 23, 1973 [21] Appl. No.: 418,178 ABSTRACT This invention relates to chlorinated derivatives of l- (2-A -imidazolinyl)-2,2-diarylcyclopropanes and their [30] Foreign Apphfauonpnomy Dam acid addition salts as new industrial products, to the 1972 United Kfngdomw' 55278/72 process for their preparation and to their therapeutic Feb. 6, 1973 United Kingdom 5774/73 application such as ami inflammatory and anti arrhythmic agents. [52] US. Cl. 260/309.6; 260/465 G; 424/273 511 Int. Cl C07d 49/34 4 (Ila-ms, No Drawings CHLORINATED DERIVATIVES OF I-( 2-A -IMIDAZOLINYL)-2,2-DIARYLCYCLOPRO- PANES The new compounds according to the invention are selected from the group comprising:

a. compounds corresponding to the general formula formula \VWWW cu in which R is as defined above, by a process distinguished by the fact that:

a. the nitrile of formula II is reacted with ethylene diamine monotosylate b. if necessary, the compound thus obtained which corresponds to the formula is subjected to a metallation reaction and the metallic derivative thus formed reacted with a halide corresponding to the formula R Hal in which I-Ial is a halogen atom and R is different from the hydrogen atom, to form a compound of formula I in which R is different from the hydrogen atom.

In a preferred embodiment, the reaction of nitrile II with ethylene diamine monotosylate is carried out at 200C without any need for a solvent; instead the reaction is simply carried out in an excess of ethylene diamine monotosylate, for example 2 moles of ethylene diamine monotosylate per mole of nitrile II.

In another preferred embodiment, the metallation reaction is carried out by means of the compound selected from a group comprising sodium hydride and organolithium compounds of the formula R Li where R is a C -C alkyl group or phenyl.

In a preferred embodiment, the metallation of a compound Ia with NaH can be carried out in hexamethyl phosphortriamide which is also known as hexametapol or I-lMPT and which corresponds to the formula This reaction takes place at around C over a period of about 6 hours.

In another preferred embodiment, the metallation of a compound la with R Li can be carried out in an inert solvent over a period of about 1 to 3 hours at a temperature of from 15 to 25C. In this case, it is possible to use a slight excess of organolithium compound, namely 1.1 to 1.2 moles of R Li per mole of la, the preferred organolithium compound being butyl lithium. Among the inert solvents that can be used for metallation with R Li, reference is made in particular to aliphatic and aromatic hydrocarbons, ethers and tetrahydrofuran. The preferred solvents for this reaction are hexane, benzene, toluene, Xylene, diethylether and tetrahydr0- furan.

The acid addition salts of the compounds of formula I are obtained by reaction with a mineral or organic acid by a method known per se. Acids suitable for this purpose include in particular hydrochloric acid, sul phuric acid, phosphoric acid, oxalic acid, succinic acid, methane sulphonic acid, cyclohexyl sulphamic acid, formic acid, aspartic acid, glutamic acid. N-acetyl aspartic acid, N-acetyl glutamic acid, ascorbic acid, maleic acid, malic acid, fumaric acid, lactic acid, benzoic acid, cinnamic acid, p-toluene sulphonic acid.

The compounds according to the invention can be used in therapeutic compositions intended in particular for the treatment of inflammation and pain, being distinguished by the fact that they contain at least one compound of formula I or one of its non-toxic acid addition salts in association with a physiologically acceptable excipient.

Other advantages and features of the invention will be apparent from the following examples in which Example 1 relates to the preparation of a nitrile of formula ll, Example 2 relates to the synthesis of a compound la according to the invention, Examples 3 and 4 relate to the metallation technique using Nal-l whilst Examples 5 and 6 relate to the metallation technique using an organolithium compound.

EXAMPLE 1 l-Cyano-2,2-di-p-chlorophenyl cyclopropane (Formula 11; R Cl) 0.55 mole of acrylonitrile are added dropwise to a solution of 0.5 mole of di-p-chlorophenyl diazomethane in 500 cc of ether. The mixture is then stirred at around 30C. The evolution of nitrogen is over after 5 hours. The solvent is evaporated and the residue distilled in vacuo.

1-(2-A -imidazolinyl)-2,2-di-pchlorophenyl cyclopro pane (Formula 1; R Cl, R, H)

A mixture of 0.5 mole of 1-cyano-2,2-di-pchlorophenyl cyclopropane and 1 mole of ethylene diamine monotosylate III is heated progressively to 200C and kept at this temperature for a period of 2 hours. The mixture is then allowed to cool and taken up in 1.2 moles of sodium hydroxide in 400 cc of water, followed by the addition of 200 cc of chloroform. The chloroform is decanted and the aqueous phase reextracted with 100 cc of chloroform.

The product is dried over sodium sulphate and the chloroform removed in vacuo.

Preparation of the hydrochloride The residue left following evaporation of the chloroform as described above is taken up in 200 cc of isopropanol, followed by the addition of ethyl chloride up to pH 1 and then by the addition of 50 cc of ether. The product is then triturated. lt crystallises, is filtered and dried, followed by recrystallisation from 90 isopropanol.

Yield 54 7c m.p. 295C (decomposition) Analysis: N 7: calculated 7.62

found 7.51

EXAMPLE 3 1-[ 2-( N-p-chlorobenzyl )-A -imidazolinyl ]-2,2- diphenyl cyclopropane cooled in an ice bath, followed by the dropwise addition, at a temperature kept at around 25C, of 0.12 mole of p-Cl-C H CH C1. After the heat effect has abated, the reaction medium is stirred for 2 hours at room temperature 15 to 25C). It is then poured onto 300 cc of water, extracted with ether, dried over magnesium sulphate and the ether removed. Preparation of the hydrochloride The evaporation residue is taken up in 50 cc of ether, ethyl chloride added up to pH 1, followed by trituration. After crystallisation, the product is filtered, washed with ether and dried and then recrystallised from a mixture of isopropanol and ether 30).

The product obtained has the following characteristics:

Yield 45 mp. 201 203C Analysis: N calculated 6.6

found 6.4

EXAMPLE 4 1-[2-(N-benzyl)-A -imidazolinyl]-2,2-di-pchlorophenyl cyclopropane (Formula I; R Cl, R, C H CH The procedure is as in Example 3, except that the l- (2-A -imidazo1inyl)-2,2-diphenyl cyclopropane is replaced by 1-(2-A -imidazoliny1)-2,2-di-p-chlorophenyl cyclopropane (0.1 mole), prepared by the method described in Example 2, and the p-Cl-C H CH- C1 by an equivalent quantity of C H CH CL Preparation of the hydrochloride The hydrochloride prepared as described in Example 3 has the following characteristics:

Yield 30 V1 m.p. 250C Analysis: N 7r calculated 6.1 1

found 6.24

EXAMPLE 5 1-[2( N-p-chlorobenzyl )-A -imidazolinyl]-2,2- diphenyl cyclopropane (Formula I; R H, R =p-Cl C H CH 0.1 1 mole (44 cc) of a 2.5 M butyl lithium solution in hexane is added at a temperature kept at around 20C to 0.1 mole of l-[2-A -imidazoliny1]-2,2-diphenyl cyclopropane in cc of anhydrous benzene, and the mixture stirred for 2 hours at ambient temperature 15 to 25C). 0.12 mole of pchlorobenzyl chloride is added dropwise to the reaction mixture at a temperature kept at around 25C. The reaction mixture is then stirred at room temperature until it is homogeneous (which takes about 2 hours), and is then heated under reflux for 3 hours. After cooling, 100 cc of water are added and the mixture stirred for 10 minutes, decanted, extracted with 200 cc of ether, dried over magnesium sulphate and the solvent evaporated in vacuo. Preparation of the succinate The evaporation residue is taken up in cc of ethanol, heated under reflux and 0.1 mole of succinic acid added while stirring. After cooling, 150 cc of ether are added and the product left standing for 2 hours, after which it is filtered, dried and recrystallised from a mixture of isopropanol and ether (80 20).

Yield Analysis:

mp. 126C calculated 5.55 found 5.51

EXAMPLE 6 1-[2-(N-benzy1)-A imidazolinyl]-2,2-di-pchlorophenyl cyclopropane 1 (Formula I; R Cl, R C H CI-l The procedure is as in Example 5, except that the 1- (2-A -imidazolinyl)-2,2-diphenyl cyclopropane is re- The evaporation residue is taken up in 200 cc of acetone, ethyl chloride added with stirring up to pH 1 and the product left standing for 3 hours, after which it is filtered, washed with acetone and dried.

Yield 67 mp. 250C Analysis: N calculated 6.1 1 found 6.17

The results of pharmacological tests carried out with the products of Examples 2, 3 and 4 are summarised in the following.

I Anti-inflammatory activity 1. Method Groups of 12 male SPF rats (OFA strain) weighing 120 to 130 g are given the products to be tested orally 2 hours and 30 minutes (half the dose each time) before the subcutaneous plantar injection of 0.05 ml of a 1 percent carrageenin solution. The volume of the rear paw into which the phlogogenic agent has been injected is measured at regular intervals. The effective dose 50 (DE is calculated at the acme of the phenomenon in the controls. The following Tables show the percentage inhibition levels at different times. 2. 4

The results are set out in Table I below.

,TABLE II mg/kg A Example Example 3 Example 4 8 22., 36. 1e I 14 36 32 35 43 3O 64 ,62' J Y 43 53 [128 64 I 36 I 65 256 '83 DE mg/kg 128 mg/kg ,60 mg/kg V0 V0 V0 m Antalgicactivity" 1. Method The products to'be treated are administered orally to groups of 6 male mice (SPF,, strain OF,) weighing 19 to 20 g.

1 hour later, the mice are injected intraperitoneally with 0.3 ml of a 0.02 percent phenyl benzoquinone solution, and the number of painful reactions (writhing of the abdomen) is counted from the 5th to the 10th minute after this treatment. Y

The following Table shows the percentage inhibition of these reactions.

2. The results are set out in Table III below.

TABLE III mg/kg Example 2 Example 3 Example 4 O z .4 '1 v. 2

DE 26 mg/kg V0 45 mg/kg V0 20 mg/kg VO IV Ulcerogenic activity 1. Method Groups of 6 male rats are put on a diet of water 18 hours before the test. The products to be tested are orally administered. 6 hours later, the stomachs of the rats are removed and examined under a binocular microscope for signs of ulceration.

2. Results The products of Examples 2, 3 and 4 do not cause any change visible under a microscope in the gastric II Anti-hyrthermal activity 1. Method mucous in oral doses of 128 to 152 mg/kg.

It can be seen from these various test that the prod- Groups of 6 male SPF rats (OFA strain) wei hi ucts of Examples 2, 3 and 4 show interesting antiin to g are sub-cutaneously injected with a 12 percent solution of brewers yeast. The products to be tested are administered 2 hours later. Temperature is measured every hour for 6 hours. The following Table shows the percentage inhibition of the reaction at the 65 thermal peak of the controls. 2. The results are set out in Table II below.

flammatory properties. The clinical tests carried out verified the indications relating to the treatment of inflammation which had been envisaged on the basis of the pharmacological tests.

The product of Example 2 in particular, administered in the form of capsules containing 200 mg of active principle or in the form of suppositories containing 300 mg of active principle, produced a reduction and even group, and R represents the chlorine atom and, where suppression of pulmonary, post-traumatic, haemorrhoi- R contains at least one chlorine atom, can represent dal and vascular inflammation. A pediatric suspension h d d containing 20 mg of active Principle in 5 m1 of a b. their pharmaceutically acceptable acid addition ventional vehicle reduced and even suppressed pulmo- Sa]ts nary inflammation arising out of an infection. A 5 per- 2. 2 A2 imidazO|iny|) 2,2 di p ch]OrOpheny1 cent 'l has an ann'mflammatory F both F clopropane and its pharmaceutically acceptable acid post-traumatic oedema and on superficial venous inaddition salts flammation. The product of Example 2 has remarkable gastric tolerance.

I claim:

I 0 3. 1- 2-( N-p-chlorobenzyl )-A -imidazolinyl -2,2- diphenyl cyclopropane and its pharmaceutically ac- 1. Chlorinated 1-(2-A -imidazolinyl)-2,2-diarylceptable acid additim Saltscyclopropanes selected from the group comprising: 4. I 1-[Z-(N-benzyl)-A -imidaz0linyI]-2,2-di-pa. compounds corresponding to the general formula chlorophenyl cyclopropane and its pharmaceutically if I. 1

in which R represents the hydrogen atom, the benzyl acceptable acid addition salts. group or a monochlorinated or polychlorinated benzyl 

1. CHLORINATED 1-(2$2-IMIDAZOLINYL)-2,2-DIARYL-CYCLOPROPANES SELECTED FROM THE GROUP COMPRISNG: A. COMPOUND SCORRESPONDING TO THE GENERAL FORMULA
 2. 1-(2- Delta 2-imidazolinyl)-2,2-di-p-chlorophenyl cyclopropane and its pharmaceutically acceptable acid addition salts.
 3. 1-(2-(N-p-chlorobenzyl)- Delta 2-imidazolinyl)-2,2-diphenyl cyclopropane and its pharmaceutically acceptable acid addition salts.
 4. 1-(2-(N-benzyl)- Delta 2-imidazolinyl)-2,2-di-p-chlorophenyl cyclopropane and its pharmaceutically acceptable acid addition salts. 